Paracetamol interaction

Rogers SM, Back DJ, Stevenson PJ, Grimmer SF, Orme ML. Paracetamol interaction with oral contraceptive steroids increased plasma concentrations of ethiny-loestradiol. Br J Clin Pharmacol 1987 23(6) 721-5. 

Albano, E., Poll, G., Charpatto, E., Biasi, F. and Dianzani, M.V. (1983). Paracetamol-stimulated lipid pexoxidation in isolated rat and mouse hepatocytes. Chem. Biol. Interact. 47, 249-263. 

The figure represents the chemical structure for paracetamol, which includes the N-(4-hydroxyphenyl) acetamide, derived from the interaction of p-aminophenol and an aqueous solution of acetic anhydride. The structure has two activating groups that make the benzene ring highly reactive toward electrophilic aromatic substitution. 

Glutathione is also implicated in the removal of toxic metabolites from the analgesic paracetamol (USA acetaminophen). Oxidative metabolism of paracetamol produces an A-hydroxy derivative, and this readily loses water to generate a reactive and toxic quinone imine, which interacts with proteins to cause cell damage. 

Figure 7.10 Metabolism of paracetamol. With therapeutic doses, paracetamol is metabolised to the glucuronide and sulphate conjugates. With higher doses these pathways become saturated and metabolism proceeds via die P-450-mediated route, with the formation of the toxic metabolite benzoquinone. This is normally metabolised by conjugation with glutathione. When glutathione is depleted benzoquinone is free to interact with cellular macromolecules, leading to cellular damage.

How analytical methods deal with interferences is one of the more ad hoc aspects of method validation. There is a variety of approaches to studying interference, from adding arbitrary amounts of a single interferent in the absence of the analyte to establish the response of the instrument to that species, to multivariate methods in which several interferents are added in a statistical protocol to reveal both main and interaction effects. The first question that needs to be answered is to what extent interferences are expected and how likely they are to affect the measurement. In testing blood for glucose by an enzyme electrode, other electroactive species that may be present are ascorbic acid (vitamin C), uric acid, and paracetamol (if this drug has been taken). However, electroactive metals (e.g., copper and silver) are unlikely to be present in blood in great quantities. Potentiometric membrane electrode sensors (ion selective electrodes), of which the pH electrode is the... 

The study of receptors has not featured as prominently in toxicology as in pharmacology. However, with some toxic effects such as the production of liver necrosis caused by paracetamol, for instance, although a dose-response relation can be demonstrated (see chap. 7), it currently seems that there may be no simple toxicant-receptor interaction in the classical sense. It may be that a specific receptor-xenobiotic interaction is not always a prerequisite for a toxic effect. Thus, the pharmacological action of volatile general anesthetics does not seem to involve a receptor, but instead the activity is well correlated with the oil-water partition coefficient. However, future detailed studies of mechanisms of toxicity will, it is hoped, reveal the existence of receptors or other types of specific targets where these are involved in toxic effects. 

This is known as Michaelis-Menten or saturation kinetics. The processes that involve specific interactions between chemicals and proteins such as plasma protein binding, active excretion from the kidney or liver via transporters, and metabolism catalyzed by enzymes can be saturated. This is because there are a specific number of binding sites that can be fully occupied at higher doses. In some cases, cofactors are required, and their concentration may be limiting (see chap. 7 for salicylate, paracetamol toxicity). These all lead to an increase in the free concentration of the chemical. Some drugs, such as phenytoin, exhibit saturation of metabolism and therefore nonlinear kinetics at therapeutic doses. Alcohol metabolism is also saturated at even normal levels of intake. Under these circumstances, the rate of... 

GAPDH is inhibited to more than 80 % by a toxic dose of paracetamol. It seems likely that the initiating events are chemical interactions and protein damage and that gene changes may arise later, as a response and as part of the repair processes. 

In six healthy women, a single dose of paracetamol 1 g significantly increased the AUC of ethinylestradiol by 22% and reduced the AUC of ethinylestradiol sulfate (353). Plasma concentrations of levonorgestrel were unaltered. This interaction could be of clinical significance in women taking oral contraceptives who take paracetamol regularly or suddenly stop taking it, but it is doubtful whether it has any practical repercussions. 

In examining a crystalline structure as revealed by diffraction experiments it is all too easy to view the crystal as a static entity and focus on what may be broadly termed attractive intermolecular interactions (dipole-dipole, hydrogen bonds, van der Waals etc., as detailed in Section 1.8) and neglect the actual mechanism by which a crystal is formed, i.e. the mechanism by which these interactions act to assemble the crystal from a non-equilibrium state in a super-saturated solution. However, it is very often nucleation phenomena that are ultimately responsible for the observed crystal structure and hence we were careful to draw a distinction between solution self-assembly and crystallisation at the beginning of this chapter. For example paracetamol, when crystallised from acetone solution gives the stable monoclinic crystal form I, but crystallisation from a molten sample in the absence of solvent... 

Diflunisal Overdose (15 g) of diflunisal leads to poisoning, which could be fatal.51 Treatment can be given by gastric lavage and supportive care. Interactions of diflunisal with indomethacin, paracetamol, antacids, benzodiazepines, and probenecid have been reported.5 Concomitant use with indomethacin should be avoided, as this could cause fatal GI complications. 

Concomitant administration of paracetamol with other hepatotoxic drugs or drugs acting on liver microsomal enzymes enhances paracetamol toxicity. Other drugs that interact with paracetamol are metoclopramide, probenecid, and cholestyramine.81... 

The paracetamol-alcohol interaction is complex acute and chronic ethanol intake has opposite effects. 

There are few clinically significant drug interactions with paracetamol. 

Despite case reports of hepatotoxicity in patients taking enzyme inducers and paracetamol concomitantly, there is currently no good evidence that the interactions are clinically significant when recommended doses of paracetamol are used [5]. However, because of the theoretical basis and the potentially severe outcome, patients taking enzyme-inducing drugs are treated with N-acetylcysteine at a reduced threshold in the event of paracetamol overdose. 

As with alcohol, there is a complex interaction between isoniazid and paracetamol, affecting the risk of hepatotoxicity [5]. 

The opioids (e.g. codeine, dextromethorphan), NSAIDs, aspirin and paracetamol found in many over-the-counter drugs have the potential for adverse drug interactions. For more details, see Over-the-Counter Drugs. 

For full details of potential interactions, see Analgesics, Paracetamol... 

Interactions. Rifampicin is a powerful enzyme inducer and speeds the metabolism of numerous drugs, including warfarin, steroid contraceptives, narcotic analgesics, oral antidiabetic agents, phenytoin and dapsone. Appropriate increase in dosage, and alternative methods of contraception, are required to compensate for increased drug metabolism (see also paracetamol overdose, p. 287). 

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